The Polycythemias

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1241 times

Chapter 28 The Polycythemias

Marina Kremyanskaya, Vesna Najfeld, John Mascarenhas, Ronald Hoffman

Table 28-1 Differential Diagnosis of the Polycythemias

Relative or Spurious Polycythemia

1. Decreased plasma volume—reduced fluid intake, marked loss of body fluids (diaphoresis, vomiting, diarrhea, “third spacing”)

2. Gaisböck syndrome

3. Overfilling of blood in collection vacuum tubes
Absolute Polycythemia

1. Secondary polycythemia

A. Acquired

Hypoxia

• Pulmonary disease
• Cyanotic congenital heart disease
• Hypoventilation syndromes: sleep apnea, Pickwickian syndrome
• High altitude
• Smokers’ polycythemia, hookah polycythemia, carbon monoxide intoxication caused by industrial exposure

Postrenal transplantation erythrocytosis

Aberrant erythropoietin production

• Tumors: renal cell carcinoma, Wilms tumor, hepatic carcinoma, uterine leiomyomata, virilizing ovarian tumors, vascular cerebellar tumors
• Miscellaneous renal and hepatic disorders: solitary renal cysts, polycystic kidney disease, renal artery stenosis hydronephrosis, viral hepatitis

Endocrine disorders: Cushing syndrome, primary aldosteronism

Androgen use

Erythropoietin use

B. Congenital Polycythemias

• Abnormal high-affinity hemoglobin variants
• Bisphosphoglycerate deficiency
• Congenital methemoglobinemia
• Chuvash polycythemia (von Hippel Lindau mutations)
• Prolyl hydroxylase mutations
• Hypoxia-inducible factor gene mutations

2. Primary polycythemias

• Primary congenital and familial polycythemia
• Polycythemia vera
image

Figure 28-1 EVOLUTION OF POLYCYTHEMIA VERA (PV).

MF, Myelofibrosis.

Table 28-2 International Working Group for Myelofibrosis Research and Recommended Treatment Criteria for Post-PV MF

Required Criteria:

1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria

2. Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)
Additional Criteria (Two Are Required):

1. Anemia or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis

2. A leukoerythroblastic peripheral blood picture

3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly

4. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)

WHO, World Health Organization.

Adapted from Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the international working group for myelofibrosis research and treatment. Leukemia 22:437, 2008.

Table 28-3 Risk Stratification in Polycythemia Vera Based on Thrombotic Risk

Risk Category Age >60 Years or History of Thrombosis Cardiovascular Risk Factors*
Low No No
Intermediate No Yes
High Yes  

*Hypertension, hypercholesterolemia, diabetes, and smoking. Extreme thrombocytosis (platelet count >1500 × 109 L−1) is a risk factor for bleeding. Its role as a risk factor for thrombosis is uncertain. An increasing leukocyte count has been identified as a novel risk factor for thrombosis, but confirmation is required.

Data from Finazzi G, Barbui T: How I treat patients with polycythemia vera. Blood 109:5104, 2007.

General Principles of Therapy

1. The etiology of erythrocytosis must be correctly categorized to be certain the patient has PV. This will avoid inappropriate exposure of patients with nonmalignant disorders to potential leukemogenic agents. To this end, a major contribution is played by incorporating a JAK2V617F and exon 12 JAK2 mutational determinations in the diagnostic workup, and in this way, early phases of PV can be recognized as well. In individuals with erythrocytosis without a JAK2 mutation, search for mutations in VHL, PHD2, HIF-1, and HIF-2 should be considered.

2. Therapy should be individualized.

3. Initially, the hematocrit should be reduced to 45% as soon as possible. The speed of phlebotomy will depend on patients’ general medical conditions (250-500 mL every other day). Elderly patients with compromised cardiovascular or pulmonary systems should be more carefully phlebotomized (twice a week), or smaller volumes of blood should be removed.

4. Hematocrit levels should be maintained at 45%.

5. The use of chemotherapeutic agents should be avoided in low-risk PV patients, and treatment with hydroxyurea or INF should be reserved for high-risk patients. Be on the look-out for toxicities from each of these agents.

6. Hyperuricemia is treated with allopurinol (100-300 mg/day).

7. Pruritus is treated empirically with cyproheptadine 4 to 16 mg/day or, if unsuccessful, INF-α therapy 3.0 × 106 units subcutaneously three times a week. A role of selective serotonin uptake inhibitors (paroxetine 20 mg/day or fluoxetine 10 mg/day) or with phototherapy has been proposed. Dramatic relief occurs with the institution of JAK2 inhibitors, and these agents should be used as a component of an experimental trial or if the patients have features that justify the diagnosis of post-PV MF syndrome.

8. Elective surgery or dental procedures should be delayed until hematocrit and platelet counts have been normalized for more than 2 months. Aspirin should be withdrawn at least 1 week before surgery. If emergency surgery is contemplated, phlebotomy and cytapheresis should be pursued.

9. Women and men who are contemplating having children should be treated by phlebotomy plus low-dose aspirin therapy (81 mg/day or with INF-α) to avoid teratogenic effects of chemotherapy. Such avoidance will also prevent deleterious effects on fertility. During pregnancy, therapy is frequently not necessary; if it is, phlebotomy plus low-dose aspirin should be exclusively used. If phlebotomy control is inadequate, treatment with INF-α should be pursued.

Algorithm for Management of Patients With Polycythemia Vera

Low-Risk Young Patients (Age <60 years) and No History of Thrombosis, Platelet Count <1.5 × 106 mm−3

Phlebotomy + low-dose aspirin (81 mg/day) to maintain hematocrit lower than 45% in males and lower than 42% in females. Aspirin should not be used in patients with histories of a hemorrhagic episode or with extreme thrombocytosis (>1.5 × 106 mm−3) or acquired von Willebrand syndrome.

↓

Thrombosis or hemorrhage

Systemic symptoms

Severe pruritus refractory to histamine antagonists

Painful splenomegaly

↓

Hydroxyurea 15-20 mg/kg (unless younger than 40 years, pregnant, intolerant to hydroxyurea; consider pegylated INF)

↓

Pegylated INF 45 to 180 µg/wk or INF – (3 × 106 units three times a week; alter dose depending on response and toxicity). Consider the use of pegylated INF, which can be administered once weekly.

↓

If platelet control is inadequate or patient cannot tolerate interferon, one option is the use of anagrelide. However, the use of this drug is controversial. In this case, supplemental phlebotomy is required to maintain hematocrit lower than 45% in males and lower than 42% in females, and the use of hydroxyurea should be considered, especially if patient continues to have thrombotic episodes.

↓

If the patient has increasing splenomegaly, systemic symptoms, or repeated thromboses despite adequate dose of hydroxyurea (2-3 g/day), start busulphan, 4 to 6 mg/day orally for 4 to 8 weeks. It should be mentioned that the sequential use of hydroxyurea and busulphan may be associated with an increased risk of leukemia. Supplemental phlebotomy may be required.

Painful splenomegaly

↓

Splenectomy + continued systemic therapy

↓

High-Risk Patients (Age >60 Years), Previous Thrombosis, Platelet Count >1.5 × 106 mm−3

Phlebotomy to hematocrit of 42% in females and 45% in males

Aspirin (81 mg/day) to be given only in patients with platelet counts <1.5 × 106 mm−2

Myelosuppressive therapy with hydroxyurea 30 mg/kg orally for 1 week

Then 15 to 20 mg/kg

↓

If patient continues to have thrombotic episodes and has extreme thrombocytosis or cannot tolerate hydroxyurea

Consider pegylated INF 45 to 180 µg/wk or add busulphan 4-6 mg/d orally for 4 to 8 weeks.

If on bisulphan, stop when blood counts are normalized or platelet count is lower than 300,000 mm−3.

Occasional supplemental phlebotomy if hematocrit is >42% in females and greater than 45% in males; when patient relapses (patient is symptomatic), initiate busulphan therapy again at same dose.

Patient Age >70 Years

Phlebotomy + low-dose aspirin + hydroxyurea

↓

No response or poor compliance

Busulphan 4 to 6 mg/day orally for 4 to 8 weeks. Stop when blood counts are normalized or platelet count is lower than 300,000 mm−3.

Related posts:

Anemia of Chronic Diseases Default ThumbnailStroke Aplastic Anemia Heme Biosynthesis and Its Disorders: Porphyrias Pain Management and Antiemetic Therapy in Hematologic Disorders Complications After Hematopoietic Stem Cell Transplantation